Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in the United States. One third of adult men and women have some form of CVD. The estimated direct and indirect cost of CVD for 2006 is $403 billion. Atherosclerosis is a major cause of severe cardiovascular diseases including myocardial ischemia, acute myocardial infarction and stroke. There are currently no clinically established non-invasive methods for staging atherosclerotic lesions and detecting vulnerable atherosclerotic plaque. As disclosed herein, novel non-invasive imaging methods targeted at a specific marker of vulnerable and advanced atherosclerotic plaque are provided. These noninvasive molecular imaging techniques can be used to assess plaque complication risk and myocardial ischemia.
Molecular tools are rapidly elucidating the molecular and cellular processes underlying atherosclerosis, myocardial ischemia and infarction. To further understand these biological processes in vivo, investigators are embracing the burgeoning field of molecular imaging. Recent technological developments including cardiac MRI, CT angiography, echocardiography with contrast agents and hybrid PET/CT and SPECT/CT scanners have extended imaging capabilities from the assessment of myocardial perfusion and function alone to permit more detailed characterization of plaques, such as advanced and vulnerable plaques and the degree of plaque remodeling.
It is widely appreciated that the oxidized form of low density lipoprotein (ox-LDL) is more important than native LDL in atherogenesis. Ox-LDL causes expression of adhesion molecules and free radical generation, injures endothelial cells, decreases constitutive nitric oxide synthase (cNOS) activity, and facilitates monocyte/macrophage adhesion on the activated endothelium. Many studies have demonstrated that these effects of ox-LDL are mediated by the interaction of ox-LDL with its receptor LOX-1.
LOX-1 is a classic type II transmembrane protein with a short intracellular cytoplasmic tail and a long extracellular domain containing a C-type lectin-like structure. LOX-1 expression is stimulated by shear stress, cytokines, angiotensin II (Ang II) and ischemia-reperfusion in endothelial cells, smooth muscle cells and macrophages. LOX-1 expression is markedly increased in atherosclerotic plaques in different animal models. Importantly, recent studies have demonstrated that LOX-1 deficiency significantly decreases the formation of atherosclerotic lesions.